This Program Project is focused on the pollutants at a designated Superfund site at the General Motors Foundry in Massena, NY. There are nine individual projects and a strong analytical core which is utilized by each project, as well as a coordinated training program with post-graduate students in epidemiology, biometry and statistics, environmental health and toxicology and civil and chemical engineering. The significance of this program is that it addresses the problems at the site using three complimentary approaches. We will obtain measurement of levels of contamination and tracing of its physical migration through surface and ground waters, sediments, soils and into the food chain to the human population. We will investigate the mechanisms of toxicity in animal model systems, focusing on neuro- and immunotoxicity. Finally, we will study remedial processes which may be occurring naturally or which can be carried out by anaerobic bacteria or supercritical fluid technology. The human population around which this proposal is focused consists of 9,000 Native Americans who inhabit Akwesasne, and whose traditional fishing waters have been contaminated with substances from the General Motor Foundry, as well as the nearly ALCOA and Reynolds Metals sites. We will determine the presence of 68 PCB congeners in breast milk, blood and urine from as many new mothers as possible in this community, and study a subset in detail in order to determine the degree and source of exposure. In both the human and animal studies we will investigate the distribution of ortho- substituted PCBs, which our previous results suggest are responsible for central nervous system effects of PCBs (reduction of cognitive potential and behavioral disturbances), and compare to distribution of the dioxin- like substances, whose toxicity is presumably mediated by the Ah receptor. We will investigate xenobiotic interactions, the effect of their combination on toxicity equivalency factors, and determine if age at exposure significantly influences toxicity. A theme of the project is that each of the PCB and PCDF congeners is a unique compound, varying in both physical and biologic properties. The overall goal of the study is to determine how these substances migrate from the site into man through plants and animals, water and soils, and what are the biologic effects of these substances and how can they be removed and inactivated.